The innate host response to bacterial pathogens is characterized by an immediate release of biologically active compounds, including monokines and cytokines. These proinflammatory molecules, which are intended to enable the host to eliminate the pathogen, may also adversely affect the host. In acute situations, the pathogen is often eliminated, with resolution of inflammation and minimal tissue damage. However, failure to control the pathogen often leads to a state of metabolic anarchy in which the inflammatory response is not controlled and significant tissue damage results. Endotoxins, produced from the outer membrane of Gram-negative bacteria, and exotoxins, released from the cell wall of Gram-positive bacteria, are known to be potent inducers of the inflammatory response. Lipopolysaccharide (LPS), extracted from the outer membrane of Gram-negative bacteria, has been identified as a principal endotoxic component.
Although the inflammatory response is mediated by a variety of secreted factors, the cytotoxic effects of LPS have been ascribed to TNF-α activity (Beutler et al., Science 229: 869-871 (1985); Tracey et al., Science 234: 470-474 (1986); Miethke et al., J. Exp. Med. 175: 91-98 (1992)). TNF-α is a pleiotropic cytokine which serves to either benefit the host or in some situations exert detrimental effects on the host (Beutler and Cerami, Nature 320: 584-588 (1986); Beutler et al., Science 232: 977-980 (1986); Beutler and Cerami, N. Engl. J. Med. 316: 379-385 (1987)). TNF-α benefits the host by helping to prevent cancer, protecting against infection, promoting tissue remodeling, and activating inflammatory responses. Conversely, in host responses which have gone awry, TNF-α mediates septic shock in chronic infections, is responsible for cachexia in cancer patients, causes inflammation in rheumatoid arthritis patients, and activates the human immunodeficiency virus. The pleiotropic effects of TNF-α are dose-dependent. Hence, the perceived need to control TNF-α production has raised interest into the understanding of the mechanisms that modulate TNF-α gene expression.
It is well known that gene transcription is controlled by DNA-binding proteins. Recently, several groups have examined the transcriptional regulation of TNF-α by various inducers, such as virus, LPS, and PMA. The human TNF-α promoter contains motifs that resemble nuclear factor kappa B (NF-κB) binding sites; however, controversy exists as to the involvement of NF-κB in TNF-α gene regulation. The nature of the nuclear factor(s) involved in the regulation of LPS-induced TNF-α gene expression in humans remains unknown.